Type2 diabetes, a world-wide epidemic afflicting close to 400M people, is caused by a failure of -cells within the islets of Langerhans to secrete sufficient insulin to compensate for insulin resistance, such as arises in obesity. Understanding the mechanisms of islet dysfunction underlying this lack of compensation and cause of diabetes is central to developing effective treatments. Many systemic circulating factors or those within the islet microenvironment that result from metabolic stress can reduce -cell function. However, the mechanisms by which they affect the regulation of insulin release, during the progression of diabetes, are poorly understood. Islets are multi-cellular micro-organs and central to the regulation of insulin release is the communication between cells. We have established an important role for gap junction channels, which electrically couple -cells in the islet, in regulating electrical activity, [Ca2+] and insulin release. Our preliminary data suggests that gap junctions are disrupted in mouse models and human cases of type2 diabetes. Importantly this disruption occurs early in disease progression and is present in pre-diabetes. Furthermore, our preliminary data also shows that gap junctions can protect against extensive islet dysfunction and cell death upon -cell-stress, via regulating [Ca2+]. Based on this evidence, we hypothesize that islet gap junctions are disrupted in pre-diabetes or early in the development of diabetes: this impacts the dynamics of insulin secretion, including reducing first phase release, but also leads to increased susceptibility of -cells to more extensive dysfunction and death during the progression of type2 diabetes. Therefore we anticipate that enhancing islet gap junction coupling will protect the islet from dysfunction and thus blunt or prevent the progression of diabetes. We will test this hypothesis through 3 specific aims: 1) determine the mechanisms(s) by which gap junctions and downstream signaling are disrupted in the islet; 2) examine how gap junctions and insulin secretion dynamics are disrupted in mouse and human models of pre-diabetes and type2 diabetes; 3) test whether enhancing gap junction coupling protects against a decline in islet function and loss of glucose control. By understanding disruptions to the main way the islet functions as a multi- cellular unit, we will characterize fundamentally new mechanisms that can underlie islet dysfunction in type2 diabetes. Thus we may also discover new and novel ways of preserving -cell function and islet. This will be important for identifying new therapeutic targets for preventative treatments for type2 diabetes.